Diamond-Blackfan anemia (DBA) is a unique example of a bone marrow failure disorder that improves with drug treatment. Glucocorticoids increase red blood cell production in most DBA patients, but the underlying mechanism of clinical efficacy was unclear until recently. I identified a phenomenon where mouse burst forming unit-erythroid (BFU-E) cells progress through a continuum of developmental states during transit-amplification; glucocorticoid treatment decreases the degree of developmental progression per cell cycle, resulting in a greater number of transit-amplifying cell divisions before the onset of erythroid terminal differentiation (Developmental Cell, 2019). Conversely, TGF? treatment of BFU-Es increases rate of developmental progression and decreases overall BFU-E proliferative capacity. My findings defined a novel developmental biology paradigm where rate of progenitor cell developmental progression regulates balance of proliferation and differentiation, and total cellular output. Insights into the mechanisms by which glucocorticoids and TGF? regulate proliferative capacity remain elusive, and the conclusions from my mouse erythropoiesis studies must be directly tested in human erythropoiesis. I will identify the target genes of glucocorticoid and TGF? signaling in BFU-Es using nascent transcriptome profiling and chromatin occupancy and architecture profiling. Furthermore, I will use single cell RNA sequencing of normal and DBA patient bone marrow hematopoietic progenitor cells to compare glucocorticoid and TGF? effects on mouse erythropoiesis and human erythropoiesis. My proposed studies will: (i) contribute broadly to our understanding of pathophysiology and treatment principles in bone marrow failure, (ii) further develop a novel field within developmental biology that arose from my earlier postdoctoral work, and (iii) provide ample opportunities for mechanistic and translational follow-up for my transition to independence. I am a physician-scientist seeking K08 support for mentored research under the guidance of Dr. Harvey Lodish and Dr. Stuart Orkin. This mentored period of 80% research and career development, and 20% clinical time, will ensure I acquire the skills required to become a successful independent principal investigator. Drs. Lodish and Orkin are internationally recognized mentors, together training >200 successful independent investigators; both received the American Society of Hematology Basic Science Mentor Award. My training will occur at two world- class institutions, the Whitehead Institute for Biomedical Research, and the Dana-Farber/Boston Children's Cancer and Blood Disorders Center. Both are rich with opportunities for young scientists to train, pursue highly impactful science, and foster long-lasting collaborations. I will also be guided by a committee of researchers that are all leaders in their fields: Drs. David Bartel (RNA biology), Peter Reddien (developmental biology), and Akiko Shimamura (bone marrow failure). The support of this K08 award will allow me to focus on maturing my research and strengthening my career development during this critical last stage of mentored training. At the conclusion of my award period, I will be optimally positioned for achieving success as an independent physician-scientist.